Diabetes is a major health and economic burden in the United States. According to statistics from the American Diabetes Association there are more than 25 million people or more than 8 percent of the population, in the US with diabetes. One of the most common complications is damage to the peripheral nervous system, a condition known as diabetic neuropathy that occurs in more than 60% of diabetics. While the precise mechanism responsible for the development of neuropathy has yet to be elucidated, it is likely mediated by a variety of metabolic responses. Cytokines are small polypeptides originally identified as communicators within the immune system but have diverse actions on many cell types including those of the nervous system. We are interested in a specific family of cytokines, the neuropoietic cytokine family, because its members are known to be expressed by both the nervous and immune systems and they are important in the response to nervous system injury and repair in normal animals. Recent studies from our laboratory indicate that the receptor subunits LIFR and gp130 are dramatically upregulated very early following the development of diabetes. In addition, we have shown that two of the cytokines (interleukin-6 and leukemia inhibitory factor) in this family are differentially regulated. We therefore hypothesize that members of this family of cytokines play a role in peripheral diabetic neuropathy and this proposal seeks to further define their role in this process. This proposal tests the hypothesis tha members of the neuropoietic cytokine family play a critical role in peripheral diabetic neuropathy. We will determine which cells in diabetic nerve express the cytokines and their receptors. We will quantify the changes in the proteins involved in the signal transduction pathway and whether these are regulated by glucose. Finally we will directly measure the response to IL-6 by administering recombinant IL-6 to diabetic wild-type and interleukin-6 knockout mice and then will quantify the levels of the proteins involved in the signal transduction cascade. The potential benefit resulting from these experiments will be to ascertain the involvement of additional mediators of peripheral neuropathy. Effective treatment of diabetic neuropathy will require an understanding of the expression and regulation of the molecular basis for nerve function. PUBLIC HEALTH RELEVANCE: Defects of the peripheral nervous system are common in patients with diabetes mellitus. More than 60% of diabetic patients will develop some form of diabetic neuropathy. Currently the cornerstone of treatment lies with the maintenance of good glucose control which is often difficult. Therefore, the development of effective treatments for diabetic neuropathy is urgently needed. Replacement or inhibition of growth factors/cytokines may be the key to ameliorating diabetic neuropathy.